PROJECT SUMMARY Chronic kidney disease is a powerful risk factor for subclinical left ventricular systolic dysfunction and incident heart failure, but the mechanisms of these relationships remain incompletely understood. The inflammasome drives renal and cardiac inflammation by activating the inflammatory cytokines interleukin-1? and interleukin-18 and the pyroptotic protein gasdermin-D. In patients with systolic heart failure or coronary artery disease, pharmacologic interleukin-1? blockade improves left ventricular systolic function and maximal exercise capacity and is associated with a trend towards fewer heart failure hospitalizations. Exogenous interleukin-18 administration to wild-type mice impairs left ventricular systolic function whereas blocking interleukin-18 after experimental myocardial infarction preserves left ventricular systolic function. Furthermore, interleukin-1??s cardiodepressant effects are mediated in part by interleukin-18, suggesting that simultaneous blockade of both cytokines would confer additional benefit beyond targeting either cytokine alone. The broad goal of this application is to prepare the principal investigator, Dr. Leo Buckley PharmD, for a career as an independent, patient-oriented researcher who studies cardiovascular pharmacology with a specific interest in preventing and treating heart failure by identifying and targeting pathways that regulate myocardial structure and function. In addition to focused coursework and seminars, Dr. Buckley will complete a series of patient-oriented studies under the guidance of an expert mentoring committee to test the hypothesis that inflammasome activity contributes to incident heart failure risk in adults with chronic kidney disease by promoting left ventricular systolic dysfunction. He will address two specific aims: (1) that increased inflammasome activity associates with left ventricular systolic dysfunction and increased risk of incident heart failure in older adults; and (2) To test the hypothesis that colchicine improves left ventricular systolic function and reduces inflammasome activity in patients with uremic cardiomyopathy. These studies will improve our knowledge of and spur further investigations into the role of inflammatory cytokines in the pathogenesis of subclinical left ventricular dysfunction and heart failure. By the conclusion of the award, Dr. Buckley will have established an independent, patient-oriented cardiovascular pharmacology research program.